Negatively regulated by controlled degradation through its antagonists including Mdm2, Mdm4 and COP1, the tumor suppressor p53 have a high turn-around rate and low physiological levels. Upon DNA damage stress, p53 is rapidly stabilized and transcriptionally regulates a broad array of genes that mediate cell cycle arrest, cellular senescence, DNA repair, and apoptosis. Accumulating evidence suggests that ATM/ATR-mediated phosphorylation of Mdm2, Mdm4 and COP1 accelerates their degradation, which may be the initial driving force to induce p53 during the early DNA damage response. When the cell returns to its normal state following DNA repair, p53 needs to be simultaneously reduced. Very little is known about how the DNA damage response is `deactivated' following repair. Recent evidence suggests that a novel protein phosphatase, Wip1 (or PPM1D), contributes to closing the activation loop initiated by ATM/ATR kinases to provide p53 a homeostatic regulation. Our preliminary results showed that Wip1 stabilizes Mdm2 by dephosphorylating its ATM targeted Ser395, resulting in decreased levels of p53. We also showed that Wip1 dephosphorylates Mdm4 and COP1 in vitro at their ATM targeting sites. If aberrantly regulated, Wip1 becomes an oncogenic phosphatase that inhibits ATM/ATR DNA damage response and p53 tumor suppressor pathways. The Wip1 gene is amplified in a number of human cancers expressing wildtype p53, suggesting it possesses oncogenic functions in tumor progression. Wip1 knockout mice are resistant to spontaneous tumors, consistent with their up-regulated p53 activity. The hypothesis to be tested is that Wip1 regulates p53 primarily through dephosphorylating its antagonists (Mdm2, Mdm4 and COP1) in the ATM/ATR DNA damage response pathway.